tbuckley/cabot-search huggingface dataset:
Landscape analysis of urothelial carcinoma (UC) by telomerase reverse transcriptase (<i>TERT</i>) alterations.
Authors: Tyler F. Stewart, Magalie Dosset, Pavel Brodskiy, Joanne Xiu, Arash Rezazadeh, Nataliya Mar, Sourat Darabi, Michael J. Demeure, Pedro C. Barata, Daniel M. Geynisman, Pooja Ghatalia, Monika Joshi, Chethan Ramamurthy, Chadi Nabhan, Elisabeth I. Heath, Hannah Carter, Maurizio Zanetti, Rana R. McKay
Journal: Journal of Clinical Oncology (2022)

4524 Background: TERT is a catalytic subunit of telomerase, the unique enzyme that confers immortality to cells and is expressed in &gt;90% of cancer cells. Mutations in the TERT promoter region (pTERTmut) are the most prevalent noncoding mutations in cancer. Recent data suggest pTERTmut are associated with improved outcomes in patients with UC treated with immune checkpoint inhibitors. We evaluated the molecular and immune landscape of UC with and without pTERTmut. Methods: UC tissue samples were analyzed for DNA alterations (NextSeq, 592 Genes; NovaSeq, WES) and mRNA expression (NovaSeq, WTS). Immune cell fraction was calculated by QuantiSeq (Finotello 2019, Genome Medicine). PD-L1 expression was assessed by immunohistochemistry (IHC) (Caris Life Sciences, Phoenix, AZ). MSI/MMR was tested by fragment analysis, IHC and NGS. TMB-H was based on a cut-off of &gt; 10 mut/MB. We compared alterations between samples with and without detected pathogenic pTERTmut. Significance was determined by Mann–Whitney U, X 2 , and Fischer-Exact and p adjusted for multiple comparisons (q) was &lt; 0.05 using Benjamini-Hochberg. Results: Overall, 1686 UC samples were analyzed, 1166 from primary lesions and 499 from a lymph node or metastatic site. pTERTmut was present in 68% of primary and 61% of metastatic tumors, and correlated with modest increase of TERT expression (1.18 fold, p=0.015). pTERTmut was associated with less frequent alterations in TP53, KMT2D, CCND1, MYC, KEAP1 and less MSI/dMMR. By contrast, pTERTmut was associated with more frequent alterations in ARID1A, TSC1, PIK3CA and TMB-H (all q&lt;0.05). Over 41% of pTERTmut were TMB-H. TERTp mutations were not associated with FGFR alterations. The frequency of co-occurring mutations was similar by specimen site. In evaluating the immune landscape (Table), pTERTmut was associated with higher expression of PD-L1 (IHC, mRNA), PD-L2 (mRNA) and TIM3 (mRNA) in tumors from primary sites (all p and q&lt;0.05), but not in metastatic sites. Investigation of tumor-associated immune cells demonstrated that pTERTmut correlated with higher percentage of M1-macrophages and CD8+ T cells in primary tumors, and was inversely-correlated with NK cells in metastatic sites (all q&lt;0.05). Conclusions: This is the largest analysis looking at the molecular and immune landscape of pTERTmut UC tumors. We observed differential patterns of DNA alterations and tumor immune microenvironment based on pTERTmut status. Further work is needed to understand differences in these molecular cohorts and the association of these data with clinical outcomes. [Table: see text]
Comparison of immune checkpoint inhibitor monotherapy versus Sorafenib in unresectable hepatocellular carcinoma.
Authors: Abigail Sy Chan, Amit Rout, Rohit Kumar
Journal: Journal of Clinical Oncology (2022)

e16160 Background: Combination immune checkpoint inhibitors (ICI) or with a vascular endothelial growth factor receptor (VEGFR) agent is now the standard 1st line (1L) therapy in patients with advanced/unresectable hepatocellular carcinoma (uHCC). Currently, there is a paucity of data on the use of ICI monotherapy when combination ICI/VEGFR is contraindicated. Therefore, we conducted a meta-analysis to evaluate the efficacy and safety outcomes of ICI monotherapy versus sorafenib in patients with uHCC in the 1L setting. Methods: A systematic search of electronic databases was conducted for randomized controlled trials comparing ICI versus sorafenib in the treatment of uHCC. Efficacy endpoints were overall survival (OS), objective response rates (ORR), and progression free survival (PFS). Safety endpoints of interests were any adverse events (AE) and &gt; grade 3 AEs. We performed random effects meta-analysis to estimate odds ratio (OR) with 95% confidence intervals for individual endpoints. Results: A total of 2 studies with 1521 patients were included in the final analysis. Compared to sorafenib, ICIs were associated with improved OS [OR 0.75; 95% confidence interval (CI) 0.6-0.94]. Similarly, ICI had increased odds of ORR [OR 2.99; 95% CI 1.93-4.62] and PFS [OR 1.41; 95% CI 1.07-1.85] compared to the sorafenib arm. In the safety analyses, ICIs were associated with reduced risk of &gt; grade 3 AE [OR 0.40; 95% CI 0.22-0.72] and any AEs [OR 0.25; 95% CI 0.12-0.55] when compared to sorafenib. Conclusions: Our meta-analysis suggests that ICI monotherapy has improved OS, PFS, ORR, and better safety profile in 1L uHCC compared to sorafenib.
Correlation of clinical outcomes with programmed death ligand-1 expression on liquid biopsy.
Authors: Sriraksha Jayananda, Mahvish Muzaffar, Praveen Namireddy, Nitika Sharma, David Meyer, Paul R. Walker
Journal: Journal of Clinical Oncology (2022)

e21050 Background: Programmed death ligand-1 (PD-L1) expression is predictive of immunotherapy benefit. However, tissue PD-L1 protein immunohistochemical testing can be fraught with tissue acquisition and heterogeneity limitations. PD-L1 expression by RNA sequencing can be performed by both tissue and plasma with tissue PD-L1 protein correlations. What has not been well characterized is the correlation of plasma cell free circulating tumor RNA (cfRNA) PD-L1 and clinical outcomes with immunotherapy. Plasma cfRNA PD-L1 expression was evaluated and correlated with immunotherapy benefit in advanced non-small cell lung cancers (NSCLC). Methods: Patients with advanced NSCLC undergoing plasma next-generation sequencing including plasma cfRNA.PD-L1 testing in a Clinical Laboratory Improvement Amendments (CLIA) and College of American pathologists (CAP) accredited laboratory were retrospectively identified and evaluated at a single institution. Plasma PD-L1 positive patients underwent a de-identified chart abstraction to identify those patients with advanced NSCLC treated with front line immunotherapy regimens and those who received cytotoxic chemotherapy alone. Results: Sixteen patients with plasma PD-L1 expression treated with front-line immunotherapy regimens including single-agent immune checkpoint inhibitors, and combinatorial chemo-immune or chemo-immune-bevacizumab regimens were assessed for overall survival (OS). Eleven patients with plasma PD-L1 expression who received chemotherapy were used as a non-immunotherapy OS comparison. Median OS for the immunotherapy treated patients was thirteen months with a thirty percent three year landmark OS versus four months median OS and a ten percent three-year landmark OS for those treated with chemotherapy alone. Comparative log-rank test p-value 0.0091 and a hazard ratio of 0.36 (95%-CI 0.13-0.99). Conclusions: Plasma cfRNA PD-L1 expression is predictive of a statistically significant survival benefit from immunotherapy treatment compared to chemotherapy in the first line treatment of advanced NSCLC. The three year landmark OS of thirty percent parallels tissue PD-L1 directed immunotherapy-based treatment outcomes. The clinical utility of plasma cfRNA PD-L1 to overcome tissue acquisition and PD-L1 protein heterogeneity limitations and to study the dynamic nature of PD-L1 expression with non-immune cancer treatments and potential immunotherapy response monitoring are undergoing ongoing research.
Clinical efficacy of laparoscopic sentinel node navigation surgery for early gastric cancer: Five-year results of SENORITA trial.
Authors: Hoon Hur, Young Joon Lee, Young-Woo Kim, Jae-Seok Min, Hong Man Yoon, Ji Yeong An, Bang Wool Eom, Gyu Seok Cho, Young-Kyu Park, Mi Ran Jung, Ji-Ho Park, Woo Jin Hyung, Sang-Ho Jeong, Myeong-Cherl Kook, Mira Han, Byung-Ho Nam, Keun Won Ryu
Journal: Journal of Clinical Oncology (2022)

4050 Background: A phase III multicenter randomized controlled clinical trial (SEntinel Node ORIented Tailored Approach [SENORITA] trial) has been performed to confirm the oncologic safety of laparoscopic sentinel node navigation surgery (LSNNS) for early gastric cancer (EGC). The results did not show the non-inferiority of LSNNS relative to laparoscopic standard gastrectomy (LSG) in terms of 3-year disease-free survival (DFS), the primary endpoint of the SENORITA trial even though the improved quality of life (QOL) in the LSNNS group. However, the long-term oncologic outcomes of LSNNS have not been compared with conventional surgery. This study was planned to investigate the comparison of LSG and LSNNS for EGC in terms of 5 years survival. Methods: We collected 5-year follow-up data of 527 patients recruited in the SENORITA trial. The overall survival (OS), disease-free survival (DFS), and recurrence pattern were evaluated in full analysis sets of both LSG (n = 269) and LSNNS (n = 258). Results: The mean follow-up period was 58.5 and 57.7 months in LSNNS and LSG groups. There was no statistically significant difference in 5-year OS (p = 0.7403) and DFS (p = 0.0561) between LSG and LSNNS. In terms of DFS, additional five events in the LSG group and 7 in LSNNS occurred after a 3-year follow-up until 5-years. Primary site recurrence in 1 LSNNS, and metachronous gastric cancer occurred in one LSG and two in LSNNS were diagnosed from 3 to 5-year follow-up period. Other organ cancer developed in two vs. three and other deaths occurred in two v s. one in each group, respectively, from 3 to 5-year follow-up. Overall survival events were 6 in LSG and 7 in LSNNS, and disease-specific death events were two patients in both groups until five years. Conclusions: Although the SENORITA trial did not show non-inferiority of LSNNS in the primary endpoint, 3-year DFS relative to LSG, the 5-year DFS and OS did not reveal the statistical difference between the two groups. Considering the benefit of LSNNS regarding the postoperative QOL, LSNNS could be recommended as an alternative treatment option of LSG for EGC. Clinical trial information: NCT01804998.
Resolution ctDx FIRST plasma assay as a companion diagnostic for adagrasib and its application to longitudinal monitoring.
Authors: Ira Pekker, Julia Pollak, Kristy Potts, PuiYee Chan, Chen-Hsun Tsai, Angela Liao, Carly Garrison, Taylor Brown, Paul Stull, Daniella Bianchi-Frias, Zhen Li, Christine Baker, Kavita Garg
Journal: Journal of Clinical Oncology (2022)

3057 Background: KRAS is one of the most commonly mutated oncogenes in cancer. There is a significant need for new treatment options for patients with non–small cell lung cancer (NSCLC) harboring the KRAS G12C mutation. Adagrasib is an investigational, highly selective, oral small molecule inhibitor of KRAS G12C that has demonstrated clinical benefit in patients with KRAS G12C–mutant NSCLC and CRC. Detection of KRAS G12C in cfDNA is minimally invasive and is of benefit to NSCLC patients, many without lesions accessible by tissue biopsy testing. Methods: Resolution ctDx FIRST is a 113 gene comprehensive genomic profiling assay that identifies oncogenic alterations including substitutions, insertions, deletions, gene fusions, and homozygous deletions using targeted NGS sequencing of cfDNA. The Resolution ctDx FIRST assay is being developed as a companion diagnostic for adagrasib in NSCLC patients of the Mirati Study 849-001. Results: The LOD95 for SNVs and indels in KRAS and EGFR at a cfDNA input level of 15ng ranged from 0.34% to 0.82%. No false positives were detected in any samples from healthy donors (N = 60). A total of 230 NSCLC plasma samples were orthogonally tested using a ddPCR assay for KRAS G12C, using 76 plasma samples from Study 849-001 where KRAS G12C positive results had previously been obtained by a tissue assay, and 154 commercially procured NSCLC samples representative of the trial population. The PPA and NPA for Resolution ctDx FIRST plasma testing relative to ddPCR assay (95% CI) were 87.0% (75.1–94.6%) and 97.6% (94.1–99.4%) respectively. Of 112 Study 849-001 patients, 71 (63.4%) were tested for KRAS G12C mutations with Resolution ctDx FIRST in pretreatment plasma samples. Seventy-four commercially procured matched tissue and plasma samples were tested by Resolution ctDx FIRST and tissue assay. The PPA and NPA for Resolution ctDx FIRST plasma testing relative to tissue assay (95% CI) were 66.2% (54.0-77.0%) and 100% (94.7-100%) respectively. The detection of EGFR variants in the Resolution ctDx FIRST assay was compared to results from a ddPCR assay for each variant. A total of 165 NSCLC plasma samples generated a total of 317 comparative valid results. PPA was 100% for EGFR L858R, 88.9% for EGFR T790M, and 91.3% for EGFR Exon 19 Deletions. NPA was 97.8% for EGFR L858R, 100% for EGFR T790M, and 100% for EGFR Exon 19 Deletions. Application of the assay in longitudinally collected NSCLC and CRC patient samples will be presented highlighting changes of VAF over time including identification of oncogenes involved in emerging resistance. Conclusions: The Resolution ctDx FIRST assay offers highly sensitive, specific, and robust test results, and meets analytical requirements for clinical applications. [Table: see text]
Association of frailty with clinical and financial outcomes of allogeneic hematopoietic stem cell transplant.
Authors: Sara Sakowitz, Ayesha Ng, Shayan Ebrahimian, Peyman Benharash, Gary J. Schiller
Journal: Journal of Clinical Oncology (2022)

7046 Background: Considered the only curative therapy for many hematological conditions, allogeneic hematopoietic stem cell transplantation (alloHSCT) is increasingly used in older patients. Yet, chronological age alone has been found to be an inaccurate predictor of posttransplant sequelae. More recently, the concept of frailty has emerged as a better marker of physiologic reserve. While formal frailty instruments have not been widely adopted due to their resource intensive nature, we applied a previously-validated coding-based approach to examine the association of frailty with in-hospital outcomes of alloHSCT. Methods: All adults (≥ 18 years) undergoing alloHSCT for hematological malignancies were identified in the 2010-2019 Nationwide Readmissions Database. The previously-validated binary Johns Hopkins Adjusted Clinical Groups indicator was used to classify patients as frail. In this algorithm, the presence of diagnoses across various domains, including malnutrition, dementia, and decubitus ulcer, constitute frailty. Regression models were developed to evaluate the independent association of frailty with in-hospital mortality, periprocedural complications, length of stay, hospitalization costs, and 30-day non-elective readmissions. Results: Of an estimated 48,161 patients, 9.8% were considered frail. Frail patients were not significantly older (51.8 ± 15.0 vs 51.6 ± 14.2, p = 0.685), but had higher Elixhauser scores (2.8 ± 1.3 vs 2.0 ± 1.3, p &lt; 0.001). After adjustment, frailty was associated with increased odds of in-hospital mortality (AOR 2.22; 95% CI 1.68-2.94; P &lt; 0.001), as well as infectious (AOR 1.44, 95% CI 1.18-1.76; P &lt; 0.001) and respiratory (AOR 1.69, 95% CI 1.41-2.02; P &lt; 0.001) complications. Frailty was also associated with greater risk of acute graft-vs-host disease (AOR 1.39, 95% CI 1.12-1.72; P = 0.003) and CMV (AOR 1.72, 95% CI 1.27-2.33; P &lt; 0.001) or invasive fungal infection (AOR 1.49, 95% CI 1.07-2.06; P = 0.017). Further, frailty was linked to increased likelihood of non-home discharge (AOR 1.29, 95% CI 1.03-1.61; P = 0.026), 30-day non-elective readmissions (AOR 1.29, 95% CI 1.11-1.50; P = 0.001), and significant increases in length of stay (+6.05 days, 95% CI 4.41-7.69; P &lt; 0.001) and costs (+$36,660, 95% CI 27,413-45,907; P &lt; 0.001). Conclusions: Among patients undergoing alloHSCT, frailty, as measured by an administrative tool, was independently associated with increased in-hospital mortality, complications and overall resource use. Inclusion of frailty in risk models may better aid benchmarking efforts and inform shared-decision making. [Table: see text]
First-in-human study of pelcitoclax (APG-1252) in combination with paclitaxel in patients (pts) with relapsed/refractory small-cell lung cancer (R/R SCLC).
Authors: Angel Qin, Gregory Peter Kalemkerian, Nisha Anjali Mohindra, Jyoti D. Patel, Christos Stelios Karapetis, Jennifer W Carlisle, Jacob Sands, Alexander I. Spira, Bo Gao, Harshad Amin, Bishnuhari Paudyal, Genevieve Frank, Xuemei Sun, Yang Xu, Cunlin Wang, Tommy Fu, Robert Winkler, Zhiyan Liang, Dajun Yang, Yifan Zhai
Journal: Journal of Clinical Oncology (2022)

e20612 Background: Targeting BCL-2/BCL-xL proteins is considered an important approach for anticancer drug development. Investigational pelcitoclax (APG-1252) as a single agent is a novel BCL-2/BCL-xL dual inhibitor, which has demonstrated synergistic antitumor activity in combination with chemotherapy preclinically through targeting both BCL-xL and MCL-1 pathways. The phase I study of pelcitoclax suggested promising antitumor activity and a favorable safety profile. Methods: The primary aim of this study was to determine the safety and preliminary efficacy of pelcitoclax combined with paclitaxel in patients with R/R SCLC. Patients received pelcitoclax 160 mg or 240 mg IV infusion on Days 1, 8, and 15 plus paclitaxel 80 mg/m 2 on Days 1 and 8 of a 21-day cycle. The primary endpoint of phase Ib was to characterize the safety and tolerability of the combination. The primary endpoint of phase 2 was the objective response rate (ORR) of pelcitoclax at the RP2D plus paclitaxel using RECIST v1.1. Results: On December 20, 2021, 28 pts (median age, 63 [range, 37-77] years) were enrolled. The median (range) duration of treatment was 84 (7-259) days. The RP2D of pelcitoclax was determined to be 240 mg. A total of 26 pts experienced any grade treatment-related adverse events (TRAEs), including anemia (32.1%); ALT or AST elevation (28.6% each); neutropenia (25%); fatigue, leukopenia, or thrombocytopenia (21.4% each); peripheral neuropathy, nausea, or alopecia (17.9% each); peripheral sensory neuropathy or decreased appetite (14.3% each); and lymphopenia, hyponatremia, or dizziness (10.7% each). A total of 15 pts had at least one ≥ grade 3-4 TRAE, and 11 (39.3%) had serious AEs. No dose-limiting toxicity was reported. A total of 5 of 20 evaluable pts (4 pts in the 240 mg cohort and 1 in the 160 mg cohort) reported PR (ORR 25%), with a median response duration of 83 days. The pharmacokinetics profile showed that pelcitoclax systemic exposure increased between 160 and 240 mg, with an average terminal half-life of 3.7 to 7.4 hours and without any drug-drug interaction. Conclusions: Pelcitoclax was well tolerated at doses of up to 240 mg/week. Treatment with pelcitoclax 240 mg and paclitaxel 80 mg/m 2 demonstrated modest antitumor activity in pts with R/R SCLC. Further clinical exploration, preferably in selected patient populations with relevant biomarkers, is warranted to fully elucidate the clinical activity of pelcitoclax. Clinical trial information: NCT04210037.
Assessment of serial serum chromogranin A (CGA) and CGA/PSA ratio and treatment response with abiraterone acetate (AA) in metastatic castration-resistant prostate cancer (mCRPC).
Authors: Akeem Ronell Lewis, Brian Addis Costello, Fernando Quevedo, Lance C. Pagliaro, Richard M. Weinshilboum, Leiwei Wang, Krishna Rani Kalari, Manish Kohli, Winston Tan, Karthik Giridhar
Journal: Journal of Clinical Oncology (2022)

e17036 Background: Elevated serum CGA is associated with an intrinsic or treatment-related neuroendocrine differentiation in men with mCRPC. We previously demonstrated that elevated serum CGA was negatively associated with OS in men with mCRPC. Fluctuations in serum CGA during mCRPC therapy is not well known. We analyzed the impact of (i) rising serum CGA and (ii) baseline CGA/PSA ratio during treatment to identify associations with AA therapy. Methods: Between June 2013 and August 2015, 92 men with mCRPC were enrolled in a prospective trial (“PROMOTE”; NCT#01953640) with uniform serum processing performed prior to initiating abiraterone acetate/prednisone (AA/P) and serially after 12 weeks of AA/P treatments. Serum CGA was measured using a homogenous automated immunofluorescent assay. Patients (pts) receiving proton pump inhibitors or with abnormal renal function were excluded due to possible false elevations of serum CGA (n = 21 excluded). All patients underwent a composite response assessment at 12-weeks with imaging/PSA/QOL questionnaires. Kaplan Meier estimates, and Cox Regression models were used to calculate association with time-to-treatment failure (TTF) analyses, defined as time from treatment initiation to AA/P discontinuation based on disease progression (BlueSky Statistics, Chicago, IL, USA). Results: Of the 71 eligible pts, 67/71 had paired baseline and 12-week CGA and 70/71 pts had a baseline and a 12-week PSA available. The median baseline CGA was 83.0ng/ml (range: 53.0 - 127.0 ng/ml), median baseline PSA was 14.4 ng/ml (range: 6.4-40.2 ng/ml), and the median TTF was 10 months (range: 6-25 months). The median CGA after 12 weeks of AA/P was 98.0 ng/ml (58.0 -148.0 ng/ml) and we observed a CGA rise in 41/67 (61.2%) pts. An increase in chromogranin was associated with a lower risk of treatment failure (HR: 0.52, p = 0.0181). The median CGA/PSA ratio was 7.8 (2.6 -16.0). An elevated pretreatment CGA/PSA ratio above the median was associated with a lower risk of treatment failure (HR: 0.54 p value = 0.0185). Conclusions: We show that an increasing chromogranin on AA/P and an elevated baseline CGA/PSA in pts with mCRPC were associated with a favorable response to AA/P. Further studies are needed to assess if rising CGA during therapy reflects neuroendocrine differentiation and may indicate a sign of treatment effect targeting the androgen susceptible cells. Clinical trial information: NCT#01953640.